testing th-302, in combination with preoperative chemoradiotherapy, in esophageal cancer.

Conditions: Esophageal Cancer

Summary: open-label, single-center phase 1 study of an investigational agent th-302 and standard chemoradiotherapy with a 3+3 dose escalation design through 3 dose levels.

rationale: neoadjuvant chemoradiotherapy followed by surgery remains the standard of care for esophageal cancer patients. both limited local response as well as distant metastases are a common cause of treatment failure. combining th-302 with chemo-radiotherapy may improve outcome by: * direct cytotoxic effect of th-302 on hypoxic cells of the primary tumor without enhancing normal tissue toxicity. * increase the sensitivity of the primary tumor to chemo-radiotherapy by decreasing the hypoxic fraction. * a bystander cytotoxic effect of th-302 on normoxic cells adjacent to hypoxic cells of the primary tumor. * a potential cytotoxic effect on micro-metastasis. objective: primary objective • to determine maximum tolerated dose (mtd) of th-302 combined with chemoradiotherapy (23 x 1.8 gy in combination with carboplatin and paclitaxel) in patients with distal esophageal or esophago-gastric junction adenocarcinoma, and consequently find the recommended phase ii dose (rp2d). secondary objective * to explore the prognostic and predictive value on outcome of the repeated hypoxia pet/ct-scan at baseline and after administration of th-302 (before start of rct). * to determine presence of anti-tumor activity with th-302 administration. * to explore the relationship between tumor hypoxia detected by the hx4 pet/ct-scans and serum biomarker expression: caix and osteopontin expression. study design: open-label, single-center phase 1 study of an investigational agent th-302 and standard chemoradiotherapy with a 3+3 dose escalation design through 3 dose levels. number of patients: 9 to18. for each of the 3 dose steps, 3 to 6 patients will be included.

Eligibility criteria:
inclusion criteria: * histologically proven adenocarcinoma of the esophagus * age \>18 years * uicc t2-4 n0-2 m0, potentially resectable disease * patient discussed at tumour board (multidisciplinary team meeting) * no evident tumor invasion in nearby regions like aorta or trachea * who performance status 0-2 * less than 10 % weight loss in the past 6 months * laboratory requirements within 7 days prior to enrollment (start chemoradiotherapy): * haematology: * haemoglobin \>10g/dl * absolute neutrophils ≥ 1.5 x 109/l * platelets ≥ 100x109/l * biochemistry: * bilirubin within institutional normal limits * ast(sgot)/alt (sgpt) ≤ 2.5 institutional upper limit * creatinine clearance ≥ 60 ml/min * willing and able to comply with the study prescriptions * no history of prior thoracic radiotherapy * no severe chronic obstructive pulmonary disease with hypoxemia or in the opinion of the investigator any physiological state leading to hypoxemia * women should not be pregnant or lactating * no known infection with hiv, hepatitis b or c or any other active infection * normal ecg with careful evaluation of qt/qtc * have given written informed consent before patient registration exclusion criteria: * recent (\< 3 months) severe cardiac disease (arrhythmia, congestive heart failure, infarction) * patients with difficult peripheral intravenous access * history of prior thoracic radiotherapy * severe chronic obstructive pulmonary disease with hypoxemia or in the opinion of the investigator any physiological state leading to hypoxemia * women who are pregnant or lactating * known infection with hiv, hepatitis b or c or any other active infection